A runner's high depends on cannabinoid receptors in mice

Abstract

Exercise is rewarding, and long-distance runners have described a runner's high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both β-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner's high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models.

Keywords: anandamide; anxiety; endocannabinoid; exercise; running.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

The effects of acute long-distance running in mice. All mice had access to running wheels for 3 d (A). After 2 d without wheels, half of the mice (RUN) were given again free access for 6 h, whereas controls (CON) remained sedentary. Mice were behaviorally tested subsequently, and RUN exhibited reduced anxiety-like behavior (B) and reduced thermal pain sensitivity (C). eCBs were increased after running (D). N = 16 controls and n = 16 runners for A–C, and n = 13 controls and n = 8 runners for D. *Significant difference, with P < 0.05. ***P < 0.001. Columns represent means + SE.

Fig. 2.

Pharmacological blockage of central CB1 receptors with AM251 prevents the reduction of anxiety in runners (RUN) (A). The running-induced reduction of thermal pain sensitivity is absent after administration of peripheral CB1 or CB2 antagonists (B). *Significant difference in post hoc test. #Only a difference on trend level P = 0.1. The group size for both tests is indicated with N on A. Columns represent means + SE.

Fig. 3.

Acute exercise reduces anxiety in GABA-CB1+/+ mice, but not in GABA- CB1−/−. GABA-CB1+/+ mice perform about 10% less wheel running before behavioral testing (A). In the dark–light test, running has no anxiolytic effect in mice with a conditional deletion of CB1 receptors on GABAergic neurons (B and C). N = 14 per group. Columns represent means + SE.

Fig. S1.

Quantification of the naloxone dosage: Because the half-life of naloxone is much shorter than the half-life of all other substances (–18), we performed a pharmacokinetic experiment in 27 mice to study plasma levels 3 and 6 h after injection to determine dosage of naloxone. Therefore, we injected 10 mice with 4 mg/kgBW and 17 mice with 2 mg/kgBW of naloxone, as described in the Materials and Methods. Mice were killed by decapitation, and serum was collected. We were aiming to achieve a naloxone dosage with serum levels higher than 0.28 ng/mL 6 h after injection because earlier studies had demonstrated that serum levels higher than 0.28 ng/mL inhibit central opioid action; namely, opioid-induced ventilatory depression (20). As expected, naloxone levels declined between 3 and 6 h after injection, and mice receiving 4 mg/kgBW had higher naloxone serum levels. A dosage of 2 mg naloxone was sufficient to achieve serum levels higher than 0.28 ng/mL 6 h after injection and was therefore chosen as the naloxone dosage in experiment 2.